The Molecular Mechanisms of Metformin’s Action on Blood Lipid Profile in Diabetic Patients

Figure 1. Chemical structures of biguanide, metformin (1,1 dimetylbiguanide) and metformin hydrochloride salt (1,1-dimethylbiguanide hydrochloride).

Figure 2. Metformin absorption and elimination. Key roles are played by the proximal small intestine (enterocyte), liver (hepatocyte) and kidney (renal tubule cell). Abbreviations: Metformin (M), Plasma membrane monoamine transporter (PMAT), Organic cation transporter 1 (OCT1), Organic cation transporter 2 (OCT2), Organic cation transporter 3 (OCT3), Carnitine/organic cation transporter (OCTN1), Multi-drug and toxin extrusion-1 transporter (MATE-1), Multi-drug and toxin extrusion2-K transporter (MATE2-K), Serotonin reuptake transporter (SERT), Human thiamine transporter (THTR-2).

Figure 3. Potential role of AMPK-activated protein kinase (AMPK) activation by metformin in decreased blood cholesterol and triacylglycerol (TAG) concentrations. AMPK, activated by metformin, inactivates via phosphorylation of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) in liver and muscle, which finally leads to decreases in blood TAG and cholesterol concentrations.

Figure 4. Metformin increases the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription. That leads to limitation of fatty acid synthesis (due to inhibition of lipogenic enzymes’ gene expression), and an increase in fatty acid oxidation (due to activation of carnitine palmitoyltransferase I gene expression). Ultimately, less TAG is formed.

Figure 5. Metformin, via suppressing ChREBP, decreases plasma cholesterol and TAG concentrations. Diminished plasma concentration of cholesterol is a result of increased cholesterol uptake by the liver, due to inhibition by metformin of PCSK9 expression; this leads to an increase in the LDL-R level. Lower plasma TAG concentration is the results of inhibition by metformin (via ChREBP) of lipogenic enzymes’ gene expression.

Figure 6. The effect of metformin on acetate (absorbed from intestines) metabolism in liver. In metformin-treated patients, acetate is slowly converted to acetyl-CoA due to lower activity of acetyl-CoA synthetase, which is inhibited via ChREBP by metformin. This leads to less cholesterol and TAG synthesis.

Figure 7. Metformin decreases angiopoetin-like 3 protein (ANGPTL3) expression, which increases the lipoprotein lipase (LPL) activity that catalyzes degradation of the TAG present in serum VLDL and chylomicrons.

Figure 8. AMPK activated by metformin decreases serum total and LDL-cholesterol concentrations via stimulation of reverse cholesterol transport.